Project Summary: Using antifungal dentures is an attractive approach to manage Candida-associated denture stomatitis (CADS), a common recurring disease among denture wearers, particularly in those who are immunocompromised or medically compromised. The effectiveness of this approach has been demonstrated in short-term studies. However, the current antifungal dentures are not effective for long-term use. After days to weeks, the antifungals released cannot reach the necessary concentrations, and inhibitory effects are lost. We propose to use rechargeable technology to create infection-responsive antifungal denture materials for long-term applications. Poly acrylic acid (PAA, a major component of glass-ionomer cements) and [unreadable]-cyclodextrin ([unreadable]-CD, a widely used FDA approved drug carrier) will be covalently bound onto denture surfaces. The negatively charged PAA will bind and slowly release cationic antifungals through ionic complexes. The release rate is expected to be infection-responsive since the colonization of Candida species will decrease pH values, which will break the ionic complexes and thereby increase the rate of antifungal release. The hydrophobic cavities of [unreadable]-CD will bind and release antifungals through inclusion complexes. This dual binding mechanism is anticipated to significantly increase the antifungal-binding capacity of the dentures. Moreover, various classes of antifungals can then be combined into one denture system through ionic and/or inclusion complexes, which is expected to markedly enhance inhibitory potency and reduce the risk of microbial resistance. After a certain period of time (e.g., weeks), the concentration of the antifungals released will decrease to suboptimal levels. However, when this happens, the dentures will be cleaned and recharged with antifungals again. Because the PAA and [unreadable]-CD are permanently attached to the dentures through covalent bonds, they will not diffuse away from the dentures. Therefore, the "new" antifungals will be bound onto the denture surfaces by forming ionic and/or inclusion complexes. The recharged dentures will again provide infection-responsive release of a sufficient amount of antifungals to inhibit Candida colonization. Thus, the new dentures will act as a "rechargeable battery" of antifungals that can be repeatedly recharged to provide long- term protection. In recharging, the antifungals can be changed/rotated to further enhance inhibitory activity and minimize the risk of microbial resistance. If successful, this technology will provide an innovative approach to controlling CADS and other dental and medical device-related infections. The proposed research is designed to establish the feasibility, effectiveness, and safety of the new approach. The specific aims are to: (1) create rechargeable infection-responsive antifungal denture materials;and (2) characterize the mechanical properties, anti-colonization and anti-biofilm activity, durability, rechargeability, biocompatibility and safety of the denture materials developed. Project Narrative: The unique features of the new approach include the rechargeability of the released antifungals to achieve long-term protection, the infection-responsive release pattern to increase the quantity of antifungals released when the drugs are most needed, and the use and rotation of multiple antifungal agents in the initial binding and subsequent recharging treatments to improve inhibitory potency and minimize the risk of microbial resistance. These advantages make the rechargeable infection-responsive antifungal approach an attractive candidate for controlling Candida colonization/biofilm formation and reducing the incidence of CADS in long- term applications among high-risk patients. In addition, the rechargeable infection-responsive approach may stimulate the development of other long-term infection-resistant dental/medical devices that will make significant contributions to improving healthcare.